Methamphetamine (MA) is remarkably addictive and relapse to excessive use is highly probable and poses serious health concerns. Genetic factors have been little studied with regard to their role in susceptibility to MA addiction or relapse. A key goal will be to utilize a validated animal model of genetically-determined high and low susceptibility to MA use to improve genetic mapping resolution and to study an already identified neuroimmune gene network that influences MA response in this genetic model. In Aim 1, in coordination with Animal Core 3, replicated sets of selected mouse lines bred for high and low voluntary consumption of MA will be produced and QTL mapping will be performed by the Biostatistics and Genetics Core 2. These mice will be used for studies proposed in Components 7, 8 and 9. In Aim 2, neurocircuitry will be examined in the selected lines, using cFos mapping after acute and repeated MA treatment, and these data will be used to identify brain regions for immune factor analysis, and will be compared to imaging results from Scientific Component 7 for brains from the MA consumption selected lines. In Aim 3, qPCR immunology arrays will be used to examine brain and peripheral blood mononuclear cell gene expression for immune specific genes using samples from selectively bred MA drinking line mice that have been acutely or repeatedly treated with MA or with saline, or are in remission. These data will be used in additional network analysis by the Biostatistics and Genetics Core 2 and compared to human peripheral gene expression results for controls, chronic MA users and user in remission. In Aim 4, cognitive, anxiety-like, and impulsivity-like traits will be examined in drug naive, acute, and repeated MA-exposed MADR mice, as well as mice in remission from MA exposure. Tissue from mice treated in the same way will be transferred to Translational Service Core 5 for analysis of immune factors and to Component 7 for imaging; half of each brain will be sent for each purpose to allow individual animal correlations to be performed. These data will also be examined for correspondence between behavior, neurocircuitry and immune system alterations. In addition, impulsivity-like measures in mice will be compared to similar measures in humans from Component 7. Finally, data collected in Component 9 will inform Component 8, with regard to traits and which of the selected lines to be studied for immunotherapeutic intervention. Cross-species analyses across components will identify key immune factors associated with chronic MA exposure (and remission) and MA-induced neuropsychiatric impairments, with the goal of ultimately identifying novel immunotherapeutic interventions.